POS0092 SPATIAL DISTRIBUTION OF DISTINCT FIBROBLAST SUBTYPES IN GIANT CELL ARTERITIS
Authors: S. Xu, W. F. Jiemy, J. C. Graver, Y. Van Sleen, K. Van der Geest, P. Heeringa, E. Brouwer, A. Boots, M. Sandovici
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Giant cell arteritis (GCA) is a systemic vasculitis of large- and medium-sized arteries which is characterized by granulomatous inflammation and vascular remodeling. The pathogenesis of GCA starts in the adventitia where fibroblasts are the major cell population. Fibroblasts are recognized for synthesizing and remodeling the extracellular matrix (ECM), but their phenotype and role in GCA-affected blood vessels is largely unknown. <h3>Objectives</h3> To explore the distribution of fibroblast phenotypes and their link to vascular remodeling in GCA. <h3>Methods</h3> Temporal artery biopsies (TABs) from patients with GCA (n=9) and controls (n=9), and aorta tissues from GCA (n=9) and atherosclerosis (AS, n=11)-related aneurysm were examined. Immunohistochemical staining for CD90 (pan-fibroblast), fibroblast activation protein alpha (FAP, activated fibroblast marker), podoplanin (immunofibroblast marker), CD248 (fibrosis-related marker), alpha-smooth muscle actin (αSMA, myofibroblast marker) was performed to evaluate the distribution of fibroblast subtypes. The expression of transforming growth factor beta (TGFβ), fibroblast growth factor 21 (FGF21), platelet derived growth factor AA (PDGFAA) and PDGFB as markers of active remodeling pathways was also determined. For each marker the percentage of positive cells was determined by Qupath 0.3.0. <h3>Results</h3> TABs from GCA patients showed increased expression of CD90, FAP, podoplanin, CD248, FGF21, PDGFAA and PDGFB in the adventitia and intima compared with the controls. Isolated higher expression of TGFβ in the adventitia and αSMA in the intima was also documented. CD90<sup>+</sup>FAP<sup>+</sup> activated fibroblasts and CD90<sup>+</sup>podoplanin<sup>+</sup> immunofibroblasts were predominantly located in the adventitia, whereas αSMA<sup>+</sup> myofibroblasts were observed mainly in the intima, and CD248<sup>+</sup> fibroblasts in the adventitia-media border and intima. High expression of FAP, CD248, FGF21 and PDGFB in the media-intima was associated with intimal hyperplasia in GCA-positive TABs. GCA-affected aortas showed different patterns: CD90<sup>+</sup>FAP<sup>+</sup> activated fibroblasts, CD90<sup>+</sup>podoplanin<sup>+</sup> immunofibroblasts and CD248<sup>+</sup> fibroblasts accumulated especially in the structurally disrupted media, which was associated with abundant expression of PDGFB and FGF21. These three fibroblast phenotypes were hardly observed in AS-affected aortas. We also observed expression of CD90, FAP, podoplanin and CD248 in the artery tertiary lymphoid organs (ATLOs) of the adventitia in GCA-affected aortas. αSMA<sup>+</sup> myofibroblasts were expressed at similar levels in GCA and AS-affected aorta tissues, being mainly located in the intima. <h3>Conclusion</h3> This study documents a distinct spatial distribution pattern of fibroblast subtypes in GCA-affected temporal arteries and aorta tissues and their association with markers of active remodeling pathways. Further research is needed to dissect the precise role of these fibroblast subtypes in the pathobiology of GCA. <h3>REFERENCES</h3> NIL. <h3>Acknowledgements</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.